Amino-alcohol derivatives

ABSTRACT

The new amino-alcohol derivatives according to the invention have the formula: ##STR1## wherein: (a) R 1  is hydrogen, an alkylthio C 1  -C 5  radical, a cycloalkylthio C 5  -C 6  radical, an alkoxy C 1  -C 5  radical, a cycloalkyloxy C 5  -C 6  radical, an alkyl C 1  -C 5  radical, a cycloalkyl C 5  -C 6  radical or a halogen atom; 
     (b) R 2  is a lower alkyl C 1  -C 3  radical; 
     (c) R 3  is an alkyl C 1  -C 18  radical, substituted or not, an alkenyl C 6  -C 18  radical substituted or not, a cycloalkyl C 5  -C 9  radical; 
     (d) R 4  is an acyl group having the formula: ##STR2##  in which R 5  represents an alkyl C 1  -C 10  substituted or not, an alkenyl C 2  -C 4 , a cycloalkyl C 3  -C 8 , a phenyl substituted or not or a cinnamyl radical, R 4  being hydrogen if R 1  is hydrogen, an alkyl, alkoxy, cycloalkoxy or cycloalkyl radical or a halogen atom.

This invention relates to amino-alcohol derivatives, more particularlyamino-alcohol esters, and salts thereof and also to the process forpreparing these derivatives, pharmaceutical compositions comprising atleast one of these derivatives, and their method of use.

Derivatives according to the invention have the general formula:##STR3## wherein: (a) R₁ is hydrogen, a linear or ramified alkylthio C₁-C₅ radical, a cycloalkylthio C₅ -C₆ radical, a linear or ramifiedalkoxy C₁ -C₅ radical, a cycloalkyloxy C₅ -C₆ radical, a linear orramified alkyl C₁ -C₅ radical, a cycloalkyl C₅ -C₆ radical or a halogenatom;

(b) R₂ is a lower alkyl C₁ -C₃ radical;

(c) R₃ is:

(c-1) a linear or ramified alkyl C₁ -C₁₈ radical;

(c-2) a linear or ramified alkyl C₁ -C₄ radical substituted by a phenyl,phenoxy or benzoyl ring, these rings being optionally substituted by atleast an alkyl C₁ -C₃ or alkoxy C₁ -C₃ group or at least a halogen atom;

(c-3) a linear or ramified alkenyl C₆ -C₁₈ radical;

(c-4) a cycloalkyl C₅ -C₉ radical;

(d) R₄ is an acyl group having the formula: ##STR4## in which R₅represents: (d-1) a linear or ramified alkyl C₁ -C₁₀ radical,

(d-2) a linear or ramified alkenyl C₂ -C₄ radical,

(d-3) a cycloalkyl C₃ -C₈ radical,

(d-4) a phenyl radical or a phenyl radical substituted by at least analkyl C₁ -C₃ or alkoxy C₁ -C₃ radical or at least a halogen atom,

(d-5) a linear or ramified alkyl C₁ -C₄ radical substituted by at leasta carbalkoxy, alkoxy C₁ -C₃, amino, acylamino, cycloalkyl C₃ -C₆,phenoxy or phenyl group, said phenyl and phenoxy rings being optionallysubstituted by at least an alkyl C₁ -C₃ or alkoxy C₁ -C₃ group or by atleast a halogen atom,

(d-6) a cinnamyl radical,

(e) R₄ may represent hydrogen when R₁ is hydrogen, a linear or ramifiedalkoxy C₁ -C₅ radical, a cycloalkyloxy C₅ -C₆ radical, a linear orramified alkyl C₁ -C₅ radical, a cycloalkyl C₅ -C₆ radical or a halogenatom.

This invention is more particularly relating to derivatives of formula Iwherein:

(a) R₁ is hydrogen or, preferably in para position, a linear or ramifiedalkylthio C₁ -C₅ radical, a cycloalkylthio C₅ -C₆ radical, a linear orramified alkoxy C₁ -C₅ radical, a cycloalkyloxy C₅ -C₆ radical, a linearor ramified alkyl C₁ -C₅ radical, a cycloalkyl C₅ -C₆ radical or ahalogen atom,

(b) R₂ represents a methyl radical,

(c) R₃ is a linear or ramified alkyl C₆ -C₁₈ radical, a linear orramified alkyl C₁ -C₄ radical substituted by a phenyl, phenoxy orp-halogenobenzoyl ring, a linear or ramified alkenyl C₆ -C₁₈ radical, acycloalkyl C₅ -C₉ radical,

(d) R₄ represents an acyl group having the formula: ##STR5## wherein R₅represents: (d-1) a linear or ramified alkyl C₁ -C₆ radical

(d-2) a cycloalkyl C₃ -C₆ radical

(d-3) a linear or ramified alkyl C₁ -C₄ radical substituted by a phenyl,p-methoxyphenyl or cyclohexyl group.

A preferred class of compounds of formula I comprises those compoundswherein:

(a) R₁ represents a linear or ramified alkylthio C₁ -C₅ radical or acycloalkylthio C₅ -C₆ radical, preferably in para position in bothcases,

(b) R₂ represents a methyl radical,

(c) R₃ represents a linear or ramified C₆ -C₁₈ radical, a linear orramified alkyl C₁ -C₄ radical substituted by a phenyl, phenoxy orp-halogenobenzoyl ring, a linear or ramified alkenyl C₆ -C₁₈ radical, acycloalkyl C₅ -C₉ radical,

(d) R₄ represents an acyl group having the formula: ##STR6## wherein R₅represents: (d-1) a linear or ramified alkyl C₁ -C₆ radical,

(d-2) a cycloalkyl C₃ -C₆ radical,

(d-3) a linear or ramified alkyl C₁ -C₄ radical substituted by a phenylgroup,

(d-4) a cyclohexylmethyl radical.

Examples of compounds according to the invention are:

1-butyryloxy-1-(4-isopropylthiophenyl)-2-n.octylaminopropane

1-cyclohexanoyloxy-1-(4-isopropylthiophenyl)-2-n.octylaminopropane

1-cyclobutanoyloxy-1-(4-isopropylthiophenyl)-2-(4-phenylbutylamino)propane

1-acetyloxy-1-(4-isopropyloxyphenyl)-2-n.octylaminopropane

1-neopentylcarbonyloxy-1-(4-isopropylthiophenyl)-2-n.octylaminopropane

p-methoxyphenylacetyloxy-1-(4-isopropylthiophenyl)-2-n.octylaminopropane.

When derivatives according to formula I are as addition salts withacids, they can be transformed into their free bases or salts with otheracids by usual processes.

The most currently used salts are addition salts with acids, moreparticularly addition salts with pharmaceutically acceptable non toxicacids, prepared with suitable inorganic acids, for example hydrochloricacid, sulfuric acid or phosphoric acid or with suitable organic acidssuch as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocycliccarboxylic or sulfonic acids, for example formic, acetic, propionic,succinic, glycolic, gluconic, glucuronic, lactic, malic, tartaric,citric, ascorbic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic,methanesulfonic, ethanesulfonic, panthotenic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic acids.

As the most active products according to the invention have twoasymmetry centers, two racemates corresponding to erythro and threoconfigurations respectively may be obtained. Both said racemates may beresolved by usual processes, for example by forming diastereoisomersalts through the action of optically active acids, such as tartaric,diacetyltartaric, tartranilic, dibenzoyltartaric, ditoluoyltartaricacids, and separation of the diastereoisomer mixture by crystallisation,distillation, chromatography, and then liberation of optically activebases from these salts.

Same processes may be used when compounds of the invention comprise morethan two asymmetry centers.

The most active derivatives of the invention may thus be used either asracemates of erythro or threo configuration, or as a mixture of bothsaid forms, or still as optically active compounds of each of both saidforms. Preferred compounds are however amino-alcohol derivatives oferythro configuration.

In general, amino-alcohol derivatives according to formula I areprepared by transforming in said derivatives a compound of the generalformula II: ##STR7## wherein Q represents a radical selected in thefollowing group: ##STR8##

In these groups, R₂ to R₅ have also the meaning such as alreadymentioned, while X represents a halogen atom, such as Cl or Br, and R₆is a protective group which can be later removed by hydrolysis orhydrogenolysis, such as benzyl, trityl, acetyl, formyl, benzhydrylgroups, the so obtained amino-alcohol or salt thereof being thenoptionally transformed into a corresponding ester.

Advantageously, amino-alcohol derivatives as esters are prepared byreacting an amino-alcohol or the corresponding salt of such anamino-alcohol corresponding to formula II, wherein Q represents:##STR9## and R₁ to R₃ have the hereabove mentioned meanings with an acidR₅ COOH or an active derivative of the latter, preferably a halide,anhydride, ester or amide of such an acid, wherein R₅ represents alinear or ramified alkyl C₁ -C₁₀ radical, a linear or ramified alkenylC₂ -C₄ radical, a cycloalkyl C₃ -C₈ radical, a substituted orunsubstituted phenyl radical, a linear or ramified alkyl C₁ -C₄ radicalsubstituted by at least a carbalkoxy, alkoxy C₁ -C₃, amino, acylamino,cycloalkyl C₅ -C₆, phenoxy, phenyl group or a phenoxy or phenyl groupsubstituted by at least a lower alkyl C₁ -C₃ or lower alkoxy C₁ -C₃group or by at least a halogen atom.

The reaction temperature is advantageously between room temperature andreflux temperature of the acid or of the active derivative thereof.

An equimolecular amount of a slight excess of the the acid or of thederivative thereof with respect to the amount of amino-alcohol can beused.

The reaction with an acid can be carried out in the presence ofesterification catalysts such as for example hydrochloric acid, sulfuricacid, thionyl chloride, phosphoric acid, phosphorus oxychloride,p-toluenesulfonic acid, benzenesulfonyl chloride, boron trifluoride andcomplexes with ethers, acid ion exchange resins, molecular sieves orphase transfer catalysts, such as quaternary ammonium salts or crowncompounds.

This reaction with an acid can also advantageously be carried out byeliminating formed water by azeotropic distillation with a suitablesolvent such as for example benzene, toluene, xylene, chloroform, carbontetrachloride or methylene chloride. In this case, esterificationcatalysts, such as previously described, may also be used. Theelimination of water formed in the reaction may also be made by workingin the presence of an anhydrous salt, for example iron, magnesium orzinc sulfate.

The reaction with an acid can also be carried out in the presence of acondensation agent, such as for example dicyclohexylcarbodiimide orN,N'-carbonyldiimidazole, preferably in solvents such as chloroform,ether, methylene chloride, methanol, benzene or carbon tetrachloride.This latter reaction may be catalysed by a basic agent such as pyridinefor example. Again in the case of reaction with an acid, the latter maybe as one of its salts, for example sodium salt or quaternary ammoniumsalt, in order to make the esterification reaction easier.

The reaction with an acid chloride will be advantageously made in asolvent such as acetonitrile, acetic acid, trifluoroacetic acid,benzene, toluene at a temperature between room temperature and refluxtemperature of the selected solvent, or without any solvent by using insuch a case an excess of acid halide or in aqueous medium in thepresence of a basic agent, such as sodium or potassium hydroxide.

This reaction can also be carried out in the presence of agents fixingthe acid halide being formed in the reaction, for example organic bases,such as pyridine, collidine, piperidine, dimethylaniline, sodiumalkoxides or inorganic bases such as carbamates, hydroxides or oxides ofalkali metals, alkaline-earth metals or magnesium.

The efficiency of the reaction with an acid halide may be improved bypreviously reacting said acid halide with a Lewis acid so as to form anacylium salt, for example CH₃ CO.sup.⊕ SbF₆.sup.⊖.

The acid halide may also be formed in situ in a selected reaction mediumby treating in the presence of an agent such as phosphorus trichloride,phosphorus oxychloride, phosphorus pentachloride, thionyl chloride oroxalyl chloride.

The reaction with an anhydride can also be carried out in solvents, suchas benzene, toluene, acetonitrile, pyridine, in the acid correspondingto the anhydride or in an excess of anhydride. This reaction may becatalysed with agents such as sulfuric acid, chlorosulfonic acids, zincchloride, acetyl chloride, sodium acetate, boric acid, ferric sulfate,alkoxides of alkali and alkaline-earth metals, pyridine, acetic acid,p-toluenesulfonic acid, perchloric acid and dimethylaniline.

The reaction can also be carried out with a mixed anhydride, for exampleby adding trifluoroacetic anhydride in the reaction medium, in order toform a very reactive compound of the kind R₅ CO--OCOCF₃.

According to a way of proceeding, anhydride could be made in situ in theselected reaction medium, for example from the acid chloride and aderivative such as benzenesulfonyl chloride.

The reaction with an ester can be carried out by using reactive estersof the kind R₅ COX wherein X is for example a p-nitrophenol ortrimethylsilyl group, in the presence of condensation agents, such asorganic or inorganic bases and organic or inorganic acids.

The reaction with an amide may also be made by using for examplecorresponding N-acyl derivatives of compounds such as acylimidazolidesor acylhydantoins, in the presence of condensation agents, such asorganic or inorganic bases.

According to a way of proceeding, a compound of the following generalformula: ##STR10## wherein R₁ to R₅ have the above-mentioned meaningscan be isomerised. The migration N→O of the acyl group R₅ CO may be madeaccording to known processes, for example by action of an inorganic acidsuch as hydrochloric acid in a solvent such as methanol or by action ofan agent such as thionyl chloride.

According to another way of proceeding, compounds of the invention canbe obtained from compounds of the following general formula: ##STR11##wherein R₁ to R₄ have the above-mentioned meanings and R₆ is aprotective group such as for example a benzyl, trityl, benzhydryl,carbobenzyloxy, trimethylsilyl group. This group R₆ may be replaced byhydrogen according to well known processes depending on the kind of thegroup R₆ and preferably by hydrogenolysis or hydrolysis.

According to another way of proceeding, a compound of the followinggeneral formula: ##STR12## may also be reacted with an amine of the kindR₃ NH₂ or R₃ R₆ NH.

R₁ to R₆ have the previously mentioned meanings and X is a halogen atomsuch as bromine for example.

The reaction is preferably carried out in a solvent such as benzene,toluene, xylene, dimethylformamide, by an extended heating in thepresence of an excess of the amine compound or of a basic agent fixingthe formed acid halide.

According to a last way of proceeding, the products of the invention canbe obtained from a compound of the following general formula: ##STR13##wherein R₁, R₂ and R₄ have the above-mentioned meanings, by transformingthe NH₂ group into a NHR₃ group either by reductive alkylation in thepresence of the suitable cetone or aldehyde or by alkylation with asuitable halide or by acylation followed by a reduction.

The amino-alcohols which are necessary for preparing esters of generalformula I and those according to the invention are preferably obtainedby usual processes, more particularly from a compound of the generalformula: ##STR14## wherein R₁, R₂, R₃ and R₆ have the previouslymentioned meanings.

This reduction may be carried out in the usual manner, most easily forexample by action of alkali metal hydrides, such as sodium borohydride,in a solvent, such as methanol or ethanol, preferably at lowtemperature, or aluminium and lithium hydride in a solvent such asdiethyl ether or tetrahydrofuran, or still by action of an aluminiumalkoxide, such as aluminium isopropoxide, in a solvent, such asisopropanol, most advantageously at the reflux of the latter. Thereduction can also be made by hydrogenation in the presence of acatalyst, such as palladium on carbon, Raney nickel, platinum oxide in asolvent, such as methanol, ethanol, dioxan, acetic acid.

Detailed preparation processes of some amino-alcohol derivativesaccording to the invention are described hereinafter. These examples aregiven for more completely illustrating particular features of theprocess according to the invention.

EXAMPLE 1 1-Acetyloxy-1-(4-isopropylthiophenyl)-2-n-octylaminopropanehydrochloride

To 15 gr (40 mol) of 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanolhydrochloride, 12,6 gr (160 mmol) of acetyl chloride are added. Heatingis provided for 1 hour at reflux temperature, then 30 ml of benzene areadded, reflux being maintained for two further hours. When cooling, theresulting solution abandons a white solid. The latter is filtered, thenrecrystallised from benzene. The product then weighs 11.5 gr (28 mmol,70%) and melt at 167.5° C.

The IR, NMR and mass spectra are in agreement with the structure.

    ______________________________________                                        Elementary analysis                                                                          C           H     N                                            ______________________________________                                        % calculated   63.5        9.2   3.4                                          % found        63.6        9.2   3.4                                          ______________________________________                                    

EXAMPLE 2 1-Butyryloxy-1-(4-isopropylthiophenyl)-2-n-octylaminopropanehydrochloride

A mixture made of 10 gr (27 mmol) of1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol hydrochloride and11.4 gr (107 mmol) of butyryl chloride is heated at reflux temperatureuntil a limpid solution is obtained. 10 ml of acetonitrile are added andreflux is maintained for about 2 hours. The solution so obtained isdiluted with 40 ml of acetonitrile before being cooled. The white solidif filtered off. After recrystallisation from acetonitrile, the productweights 6.4 gr (14 mmol, 52%) and has a melting point of 104.1° C.

The IR, NMR and mass spectra confirm the structure.

    ______________________________________                                        Elementary analysis                                                                          C           H     N                                            ______________________________________                                        % calculated   64.9        9.5   3.2                                          % found        64.6        9.3   3.0                                          ______________________________________                                    

EXAMPLE 3 1-Acetyloxy-1-(4-isopropylthiophenyl)-2-n-octylaminobutanehydrochloride

To 20 ml of acetonitrile, 5 gr (13 mmol) of1-(4-isopropylthiophenyl)-2-n-octylamino-1-butanol hydrochloride and 5.3g (52 mmol) of acetic anhydride are added successively. The mixture isrefluxed for 2.5 hours. When cooling, it abandons a white solid. Thelatter is filtered off and twice recrystallised from acetonitrile.

Weight: 4.1 g (9.4 mmol, 72%); M.P. : 135.0° C.

The IR, NMR and mass spectra confirm the structure.

    ______________________________________                                        Elementary analysis                                                                          C           H     N                                            ______________________________________                                        % calculated   64.2        9.1   3.3                                          % found        64.0        9.0   3.5                                          ______________________________________                                    

EXAMPLE 4 1-(p-n-Butyloxyphenyl)-1-sec-butyryloxy-2-n-octylaminopropane

A mixture made of 5 gr (13.5 mmol) of1-(butyloxyphenyl)-2-(n-octylamino)-1-propanol hydrochloride, 5.7 gr(53.8 mmol) of isobutyric acid chloride and 20 ml of acetonitrile isheated for 1 hour at the reflux temperature. The final medium is dryevaporated under reduced pressure. The residual greenish oil is taken upwith 150 ml of petroleum ether (B.P.: 100°-140° C.) and the so obtainedsolution is stirred for 15 minutes at 78° C. The appearing white solidis filtered off, washed with ether and recrystallised from acetonitrile.

4.3 gr (9.6 mmol; 72%) of hydrochloride of the desired ester, M.P.(°C.): 110.5 is obtained.

    ______________________________________                                        Elementary analysis                                                                          C           H     N                                            ______________________________________                                        % calculated   67.9        10.0  3.2                                          % found        67.8        10.1  3.5                                          ______________________________________                                    

The spectral data (IR, NMR) confirm the structure.

EXAMPLE 5 1-(4-Isopropoxyphenyl)-2-(4-phenylbutylamino)-1-propanol

A solution of 200 gr (1.33 mol) of 1-(4-hydroxyphenyl)-1-propanone in860 ml of methanol containing 75 gr (1.33 mol) of potassium hydroxide isheated at reflux temperature. Then 172 gr (1.40 mol) of isopropylbromide are slowly added. After the addition is complete, reflux isstill maintained for 20 hours. The medium, when at room temperature, isadded with 1 liter of water and extracted with chloroform.

The extract is dried (MgSO₄) and dry evaporated under reduced pressure.The light brown oil so obtained is distilled under vacuum. The1-(4-isopropoxyphenyl)-1-propanone is collected between 119° and 127° C.under a pressure of 2 Torr. The product weighs 190 gr (1.03 mol; 77%).

To 300 ml of methanol added with 2 gr of aluminium chloride, 204 gr(1.06 mol) of the preceding cetone are added. Heating is made with abath maintained at 40° C., then 180 gr (1.12 mol) of bromine are addeddropwise.

One stirs for 1 hour at room temperature, then 200 ml of water areadded. Extraction is made with chloroform and the extract is washed witha 5% aqueous sodium hydrogen carbonate solution, then with water, dried(MgSO₄) and dry evaporated under reduced pressure. The2-bromo-1-(4-isopropoxyphenyl)-1-propanone is purified by distillation(BP: 140°-160° C./1.7 Torr), and recrystallisation from hexane. M.P.:52.4° C.; weight: 203 gr (0.75 mol; 71%).

A mixture made of 70 ml of methanol, 18.0 gr (67 mmol) of the brominatedketone, 7.08 gr (70 mmol) of thiethylamine and 11.9 gr (80 mmol) of4-phenylbutylamine is heated for 2 hours at reflux temperature, thenbrought back to room temperature before being cooled by means of an icebath. A solution of 2.1 gr (54 mmol) of sodium borohydride dissolved in20 ml of water alkalinised, by a drop of 10% aqueous sodium hydroxide isslowly added. One stirs for one additional hour at room temperature,then the mixture is dry evaporated under reduced pressure. The residueis partitionned between water and chloroform. The organic phase, driedwith MgSO₄ is then also evaporated. The oily residue is recrystallisedfrom acetonitrile and then weighs 14.5 gr (42 mmol; 63%) M.P.: 92.2° C.

The IR, NMR and mass spectra are in agreement with the structure.

    ______________________________________                                        Elementary analysis                                                                          C           H     N                                            ______________________________________                                        % calculated   77.4        9.2   4.1                                          % found        77.4        9.1   4.1                                          ______________________________________                                    

The embodiment of process according to the invention which is the mostinteresting from an industrial point of view for preparing derivativesaccording to the invention as esters is the variant consisting ofreacting a corresponding amino-alcohol or a salt thereof with an acid R₅COOH or with a reactive derivative of an acid such as hereabovedescribed with more details. It is, however, to be noted that suchesters can also advantageously be prepared according to the otherembodiments of the process according to the invention, such as describedhereinabove.

The melting points of the derivatives described in the Examples and ofother derivatives prepared according to the invention are given in thefollowing Table.

    __________________________________________________________________________     ##STR15##                                                                    No  R.sub.1                                                                              R.sub.2                                                                          NHR.sub.3          R.sub.4     MP (°C.).sup.(1)(2)       __________________________________________________________________________    1   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COC(CH.sub.3).sub.3                                                                       109.0 (isopropanol)              2   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.2 CH.sub.3                                                                       143.5 (cyclohexane)              3   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.3  167.7 (benzene)                  4   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH(CH.sub.3).sub.2                                                                      104.9 (cyclohexane)              5   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              CO(CH.sub.2).sub.6 CH.sub.3                                                               109.7 (CH.sub.3 CN)              6   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              CO(CH.sub.2).sub.2 CH.sub.3                                                               140.1 (CH.sub.3 CN)              7   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR16##  132.4 (CH.sub.3 CN)              8   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR17##  131.8 (CH.sub.3 CN)              9   4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR18##  145.6 (CH.sub.3 CN)              10  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR19##                                                                                        ##STR20##  150.6 (AcOEt)                    11                                                                                 ##STR21##                                                                           CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.2 CH.sub.3                                                                       146.3 (AcOEt)                    12  4-CH.sub.3 S                                                                         CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH(CH.sub.3).sub.2                                                                      109.5 (AcOEt)                    13  4-isoC.sub.3 H.sub.7 S                                                               C.sub.2 H.sub.5                                                                  NHnC.sub.8 H.sub.17                                                                              COCH.sub.3  135.0 (CH.sub.3 CN)              14  4-isoC.sub.4 H.sub.9 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR22##  119.2 (cyclohexane)              15                                                                                 ##STR23##                                                                           CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.3  162.3 (CH.sub.3 CN)              16  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub. 10 H.sub.21                                                                            COCH(CH.sub.3).sub.2                                                                      104.7 (CH.sub.3 CN)              17  4-C.sub.2 H.sub.5 S                                                                  CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.2 CH.sub.3                                                                       111.7 (CH.sub.3 CN)              18  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.3  149.6 (CH.sub.3 CN)              19  4-nC.sub.4 H.sub.9 O                                                                 CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH(CH.sub.3).sub.2                                                                      110.5 (CH.sub.3 CN)              20  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                          ##STR24##                                                                                        ##STR25##  163.9 (isopropanol)              21  4-isoC.sub.3 H.sub.7                                                                 CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.2 CH.sub.3                                                                       137.6 (CH.sub.3 CN)              22  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR26##         COCH(CH.sub.3).sub.2                                                                      167.0 (isopropanol)              23  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR27##         CO(CH.sub.2).sub.2 CH.sub.3                                                               149.5 (AcOEt)                    24  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR28##         CO(CH.sub.2).sub.2 CH.sub.3                                                               148.7 (AcOEt)                    25  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR29##         COCH.sub.3  142.9 (AcOEt)                    26  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR30##         COCH(CH.sub.3).sub.2                                                                      128.3 (AcOEt)                    27  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR31##         COCH.sub.3  160.0 (isopropanol)              28  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR32##  159.8 (AcOEt)                    29  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR33##  148.6 (CH.sub.3 CN) (threo)      30  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.2 C(CH.sub.3).sub.3                                                              147.8 (CH.sub.3 CN)              31  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              CO(CH.sub.2).sub.4 COOCH.sub.3                                                            127.8 (CH.sub.3 CN)              32  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR34##  132.2 (CH.sub.3 CN)              33  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR35##  162 (AcOEt)                      34  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR36##  129.6 (CH.sub.3 CN)              35  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR37##  138.0 (CH.sub.3 CN)              36  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR38##  114.6 (CH.sub.3 CN)              37  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR39##  152.1 (CH.sub.3 CN)              38  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR40##  172.7 (AcOEt)                    39  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHisoC.sub.3 H.sub.7                                                                              ##STR41##  143.5 (AcOEt)                    40  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHisoC.sub.3 H.sub.7                                                                             COCH.sub.2 CH.sub.3                                                                       161.2 (AcOEt)                    41  4-OCH.sub.3                                                                          CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR42##  155.5 (MeOH/Et.sub.2 O)          42  H      CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.3  136.0 (MeOH/Et.sub.2 O)          43  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR43##         COCH.sub.3  158.1 (AcOEt)                    44  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHcycloC.sub.8 H.sub.15                                                                           ##STR44##  198.3 (AcOEt)                    45  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.18 H.sub.37                                                                             COCH.sub.3  131.8 (CH.sub.3 CN)              46  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.18 H.sub.37                                                                              ##STR45##  133.6 (CH.sub.3 CN)              47  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NH(CH.sub.2).sub.8CHCHnC.sub.8 H.sub.17                                                          COCH.sub.2 CH.sub.3                                                                       189.5 (CH.sub.3 CN)              48  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR46##         COCH.sub.3  188.0 (CH.sub.3 CN)              49  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHCH(CH.sub.3)nC.sub.6 H.sub.13                                                                  COCH.sub.3  153.9 (CH.sub.3 CN)              50  4-Cl   CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR47##  140.1 (AcOEt)                    51  4-Cl   CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH(CH.sub.3).sub.2                                                                      128.1 (AcOEt)                    52  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR48##         COCH.sub.2 CH.sub.3                                                                       oil; ν.sub.C═O 1745                                                    cm.sup.-1                        53  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NH(CH.sub.2).sub.9CHCH.sub.2                                                                      ##STR49##  31.4 (CH.sub.3 CN)               54  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NH(CH.sub.2).sub.9CHCH.sub.2                                                                     COCH.sub.3  oil; ν.sub.C═O 1742                                                    cm.sup.-1                        55  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NH(CH.sub.2).sub.8 CHCHnC.sub.8 H.sub.17                                                         COCH(CH.sub.3).sub.2                                                                      158.9 (CH.sub.3 CN)              56  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR50##         COCH.sub.2 C(CH.sub.3).sub.3                                                              132.9 (AcOEt)                    57  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                          ##STR51##         COCH.sub.3  141.0 (CH.sub.3 CN)              58  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCHCHCH.sub.3                                                                            174.7 (AcOEt)                    59  2-OCH.sub.3                                                                          CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.3  127.8 (acetone)                  60  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHcycloC.sub.6 H.sub.11                                                                          COCH.sub.3  203.5 (MeOH/Et.sub.2 O)          61  3-Br   CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.3  148.6 (AcOEt)                    62  3-Br   CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR52##  149.9 (AcOEt)                    63  4-CH.sub.3                                                                           CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.3  139.3 (AcOEt)                    64  4-CH.sub.3                                                                           CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH(CH.sub.3).sub.2                                                                      121.1 (AcOEt)                    65  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NHnC.sub.12 H.sub.25                                                                             COCH.sub.2 CH.sub.3                                                                       100.6 (AcOEt)                    66                                                                                 ##STR53##                                                                           CH.sub.3                                                                          ##STR54##         COCH(CH.sub.3).sub.2                                                                      153.4 (AcOEt)                    67                                                                                 ##STR55##                                                                           CH.sub.3                                                                          ##STR56##                                                                                        ##STR57##  (threo) 148.2 (AcOEt)            68  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHcycloC.sub.6 H.sub.11                                                                          COCH(CH.sub.3).sub.2                                                                      184.7 (acetone)                  69  2-CH.sub.3 O                                                                         CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COCH.sub.2 C(CH.sub.3).sub.3                                                              125.1 (acetone)                  70  4-CH.sub.3 O                                                                         CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              COC(CH.sub.3).sub.3                                                                       122.5 (acetone)                  71                                                                                 ##STR58##                                                                           CH.sub.3                                                                          ##STR59##         COCH.sub.3  179.8 (acetone)                  72  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR60##  (threo) 126.8 (isopropanol)      73  4-isoC.sub.3 H.sub.7 S                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                               ##STR61##  oil; ν.sub.C═O 1725                                                    cm.sup.-1                        74  4-CH.sub.3 O                                                                         CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           228.5 (MeOHacetone)              75  4-CH.sub.3                                                                           CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           237.1 (MeOHacetone)              76  H      CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           219.0 (MeOHacetone)              77  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           230.9 (EtOHether)                78  4-isoC.sub.4 H.sub.9 O                                                               CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           78.9 (Hexane).sup.(3)            79  4-isoC.sub.4 H.sub.9 O                                                               CH.sub.3                                                                         NHnC.sub.6 H.sub.13                                                                              H           79.8 (acetone).sup.(3)           80  4-isoC.sub.3 H.sub.7                                                                 CH.sub.3                                                                         NHnC.sub.6 H.sub.13                                                                              H           66.6 (CH.sub.3 CN).sup.(3)       81  4-isoC.sub.3 H.sub.7                                                                 CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           232.5 (EtOH)                     82  4-isoC.sub.3 H.sub.7                                                                 CH.sub.3                                                                         NHnC.sub.12 H.sub.25                                                                             H           64.1 (CH.sub.3 CN).sup.(3)       83  H      CH.sub.3                                                                         NHnC.sub.6 H.sub.13                                                                              H           57.8 (CH.sub.3 CN).sup.(3)       84  4-CH.sub.3 O                                                                         CH.sub.3                                                                         NHnC.sub.6 H.sub.13                                                                              H           219.7 (EtOH)                     85  4-Cl   CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           73.0 (hexane).sup.(3)            86  H      CH.sub.3                                                                         NHnC.sub.12 H.sub.25                                                                             H           57.5 (CH.sub.3 CN).sup.(3)       87  4-Cl   CH.sub.3                                                                         NHnC.sub.12 H.sub.25                                                                             H           228.0 (isopropanol)              88  4-CH.sub.3 O                                                                         CH.sub.3                                                                         NHnC.sub.12 H.sub.25                                                                             H           219.3 (EtOH)                     89  4-CH.sub.3 O                                                                         CH.sub.3                                                                         NHnC.sub.16 H.sub.33                                                                             H           219.7 (EtOH)                     90  H      CH.sub.3                                                                         NHnC.sub.16 H.sub.33                                                                             H           221.3 (EtOH)                     91  4-nC.sub.4 H.sub.9 O                                                                 CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           65.6 (CH.sub.3 CN).sup.(3)       92  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NHnC.sub.6 H.sub.13                                                                              H           61.8 (CH.sub.3 CN).sup.(3)       93  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NHnC.sub.10 H.sub.21                                                                             H           67.3 (CH.sub.3 CN).sup.(3)       94  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                          ##STR62##         H           92.2 (CH.sub.3 CN).sup.(3)       95  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NHnC.sub.12 H.sub.25                                                                             H           71.7 (CH.sub.3 CN).sup.(3)       96  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NH(CH.sub.2).sub.9 CHCH.sub.2                                                                    H           227.3 (EtOH)                     97  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NHnC.sub.14 H.sub.29                                            98  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NH(CH.sub.2).sub.8 CHCHnC.sub.8 H.sub.17                                                         H           202.7 (EtOHether)                99  4-isoC.sub.3 H.sub.7 O                                                               CH.sub.3                                                                         NHnC.sub.16 H.sub.33                                                                             H           79.4 (CH.sub.3 CN).sup.(3)       100 2-CH.sub.3 O                                                                         CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           167.0 (MeOHether)                101                                                                                ##STR63##                                                                           CH.sub.3                                                                          ##STR64##         H           129.7 (cyclohexane).sup.(3)      102 3-Br   CH.sub.3                                                                         NHnC.sub.8 H.sub.17                                                                              H           103.9 (Hexane).sup.(3)           103                                                                                ##STR65##                                                                           CH.sub.3                                                                          ##STR66##         H           104.5 (MeOH).sup.(3)             __________________________________________________________________________     .sup.(1) the recrystallization solvent is given between brackets; the         indicated melting point is that of the hydrochloride.                         .sup.(2) the elementary analyses were made for C, H, N and are in             agreement with theoretical values.                                            .sup.(3) melting point of the free base.                                 

The products according to the invention have various pharmaceuticalactivities, mainly on the cardiovascular system.

Their antihypertensive activity was tested by oral administration tonon-anesthetized, spontaneously hypertensive rats, on which the systolicarterial pressure is measured at the level of the median coccygealartery by means of a plethysmographic method (J. Roba, G. Lambelin, A.F. De Schaepdryver, Arch. int. Pharmacodyn., 200, 182, 1972). Thearterial pressure was measured every 30 minutes from two hours before tothree hours after oral administration of 60 mgr/kg of the testedproducts or of a placebo (1% tragacanth gum mucilage). When being ofinterest, the products were tested at other doses under similarconditions. Only rats having a systolic pressure of 180 to 220 mm Hgwere used. Two rats were used for each product. The treatments were madewithout the knowledge of the person making the measures. Theantihypertensive effects were rated as follows:

0: reduction <10 mm Hg

+: reduction of 10 to 20 mm Hg

++: reduction of 20 to 30 mm Hg

+++: reduction of 30 to 50 mm Hg

++++: reduction >50 mm Hg

Under the test conditions, α-methyldopa was rated +++ at 100 mgr/kg,reserpine +++ at 3 mgr/kg and guanethidine +++ at 60 mgr/kg.

Products 8, 7, 10, 27, 25, 24, 18, 19, 20, 30, 34, 35, 37, 43 and 94have shown a suitable antihypertensive activity.

The peripheral vasodilator activity of the products according to theinvention was measured on anaesthetized dog at the level of the femoralarterial circulation. To this end, the femoral artery the collaterals ofwhich were ligaturated was perfused with a constant flow rate of bloodtaken from aorta. Thus the perfusion pressure measured at the level ofthe femoral artery, varied as a function of the resistance of perfusedarea. The tested products and the corresponding solvents were directlyinjected in the system at the dose of 30 μg/kg. The blood circulationrate being maintained constant, a vasodilation was thus measured by adecrease of the perfusion pressure. The latter is rated in comparisonwith the action of papaverine considered as standard and injected onceper group of 4 products.

When being of interest, the products were tested at other doses underthe same conditions. The vasodilation activity was rated as follows:

0: inactive (reduction <10 mm Hg)

+: 1/3 of the papaverine activity

++: 2/3 of the papaverine activity

+++: activity equal to that of papaverine (i.e. 30 to 40 mm Hg)

++++: activity higher than that of papaverine.

Amongst the products according to the invention, compounds 3, 4, 6, 9,15, 18, 20, 23, 26, 27, 74, 78, 79, 81, 82, 83, 85 and 91 have shown aperipheral vasodilator activity which is at least equal to that ofpapaverine.

The antispasmodic activity of the products according to the inventionwas tested against contractions of guinea pig ileum, such as induced byhistamine and acetylcholine. These tests allow to reveal anantihistaminic activity, an anticholinergic activity or a musculotropicantispasmodic activity. The response to the contracting agent(submaximum concentration) was repeated every 5 minutes before and afterinjection of increasing doses of the tested products (10⁻⁸ to 10⁻⁵ M).The various doses were added at intervals of 20 minutes or of the timenecessary to the development of the maximum effect.

The percentage of inhibition under the influence of tested products wascalculated and the theoretical concentration ensuring 50% inhibition wasgraphically determined for each experience. These values were expressedas -log IC₅₀ (M). The standard value for papaverine was 4.50, namely aneffective concentration of 30 μM.

All the products according to the invention have some antispasmodicactivity of musculotrope type, namely without anticholinergic ofantihistaminic component.

Compounds 1, 2, 3, 4, 6, 9, 10, 11, 15, 18, 20, 22, 23, 24, 26, 27, 28,29, 30, 31, 32, 78, 81, 83, 85, 88 and 91 have IC₅₀ values higher than6, corresponding to concentrations lower than 1 μM.

The effect on the in vitro induced lipolysis in the epididymal fat ofthe rat was measured by colorimetry of fatty acids liberated during thetissue incubation under the experimental conditions such as describedhereinafter.

Male Sprague-Dawley rats weighing about 250 gr were sacrified bycervical dislocation after a fasting period of 18 hours. The quicklytaken-off epididymal fat was placed in a Krebs-Ringer phosphate bufferat pH 7.4, containing 1% albumin.

The tissue was cut into fragments of ±20 mgr, which were dried on filterpaper and homogeneously distributed in groups of ±150 mgr weighed withprecision. Each group was pre-incubated (15 minutes, 37° C., stirring)in 5 ml of Krebs-Ringer phosphate buffer (pH 7.4) containing 7% ofbovine albumin and the product to be tested.

After pre-incubation, 1 ml of the medium is taken off for determiningthe amount of basic lipolysis. The induction agent in solution in 0.1 mlof phosphate buffer is then added to 4 ml of the remaining medium andafter incubation of 90 minutes under the same conditions, liberatedfatty acids are titrated in 1 ml of medium according to a variant of thecolorimetric method of W. G. Duncombe (Biochem. J., 83, 6P, 1962;Biochem. J., 88, 7-10, 1963; Clin. Chem. Acta, 9, 122-125, 1964).

Under the experimental conditions, compounds 1, 74, 75 and 76 reveal asbeing active.

The blood platelet aggregation was studied according to the Born Method(J. Physiol., 168, 178, 1963). Nine volumes of human venous blood weretaken off and anticoagulated with one volume of a trisodium citratesolution (0.129 M). The blood was centrifuged at 200 g for 10 minutes(22° C.) for preparing the platelet rich plasma (PRP). Methanol oracetone was used in order to obtain 2×10⁻² M solutions of the variousinvolved products, 24 μl of each product were added to 300 μl of PRP.For controls, 24 μl of the various hereinabove mentioned solvents wereused. The products were pre-incubated in the presence of PRP for 4minutes at 37° C. under continuous stirring (1100 rpm). After thisincubation period, the platelet aggregation was induced by addition of100 μl of thrombofax or collagen. The aggregation phenomenon wasquantified by graphical determination of the aggregation amplitude (A).

The inhibition percentage of the agglutination amplitude was calculatedas follows:

A (% inhibition): 100-(A_(x) /A_(o))×100

A_(x) : value of aggregation amplitude in the presence of examinedproducts

A_(o) : value of aggregation amplitude for controls

Under these experimental conditions, compounds 3 and 30 show a stronganti-aggregation effect.

The acute toxicity of the products according to the invention was alsodetermined after oral administration of a 1% tragacanth gum mucilage tomale mice (Charles River CD 1 fasting of 18 hours).

Groups of 10 mice were used and received one of the following doses:500, 1000, 1500, 2000 or 4000 mgr/kg. The behaviour of the animals wasstudied 2 and 6 hours after administration, and after 24 hours or evenmore in case of persistent symptoms. The behaviour examination wascarried out according to a method deriving from that of Irwin (GordonResearch Conf. on Medicinal Chem., 133, 1959). The mortalities wereregistered for the period of 14 days following the treatment. The LD₅₀values were calculated according to the Litchfield and Wilcoxon method(J. Pharmacol., Exp. Ther., 96, 99, 1949) and expressed as mgr/kg.

The products according to the invention are not very toxic. The LD₅₀ areabove 3000 mgr/kg in most cases.

The observed behaviour modifications mainly consist in tranquillizingaccompanied with sedation at higher doses.

From the preceeding, it results that compounds according to theinvention, while being not very toxic, are generally endowed withactivities on the cardiovascular system, in particular antispasmodic,antihypertensive, peripheral vasodilation activities, a protectingactivity against myocardium anoxia, hypolipidemic, normolipoproteinemic,antithrombotic activities, an inhibition activity against plateletaggregation and/or tranquillizing activities, and are more particularlyused in the treatment of hypertension and cardiovascular affections,such as atherosclerosis.

Preferably, the derivatives according to the invention as amino-alcoholesters are particularly useful due to their pronounced antihypertensiveactivities by comparison with those of corresponding amino-alcohols.

The active compounds according to the invention may be administrated inassociation with various pharmaceutical excipients orally, parenterallyor rectally.

For oral administration, pills, granules, tablets, capsules, solutions,syrups, emulsions or suspensions containing usual additives orexcipients in galenic pharmacy will be used.

For parenteral administration, sterile water or an oil will be used,such as peanut oil or ethyl oleate. For rectal administration,suppositories or rectal capsules will be used.

These active compounds may be used alone or in association with otheractive products having a similar or different activity.

The products according to the invention may be used as different forms.The following examples are not limitative and relate to galenicformulations containing as active product, designated by "A"hereinafter, one of the following compounds:

1-neopentylcarbonyloxy-1-(4-isopropylthiophenyl)-2-n-octylaminopropane(hydrochloride)

1-butyryloxy-1-(4-isopropylthiophenyl)-2-n-octylaminopropane(hydrochloride)

1-(4-methoxyphenyl)-2-n-octylamino-1-propanol.

1-(4-isopropylphenyl)-2-n-octylamino-1-propanol.

1-(4-butoxyphenyl)-2-n-octylamino-1-propanol.

    ______________________________________                                        Intramuscular injection                                                       A                        10     mg                                            Isopropyl Myristate      0.75   ml                                            Peanut oil, q.s. ad      3      ml                                            A                        10     mg                                            D-glucuronic acid        6      mg                                            Benzyl alcohol           50     mg                                            Distilled water, q.s. ad 5      ml                                            A                        10     mg                                            Ethyl alcohol            0.50   ml                                            Polyethylene glycol 400  0.25   ml                                            Propylene glycol         0.50   ml                                            10% acetic acid          0.125  ml                                            70% sorbitol             0.75   ml                                            Distilled water, q.s. ad 3      ml                                            Solution for oral administration.                                             A                        5      mg                                            Ethylic alcohol          0.1    ml                                            Propylene glycol         0.05   ml                                            10% acetic acid          0.05   ml                                            Simple syrup (65% saccharose)q.s. ad                                                                   1      ml                                            A                        5      mg                                            Ethyl alcohol            0.2    ml                                            10% acetic acid          0.04   ml                                            Simple syrup, q.s. ad    1      ml                                            A                        10     mg                                            Ethyl alcohol            0.25   ml                                            10% acetic acid          0.04   ml                                            Simple syrup, q.s. ad    1      ml                                            Tablets.                                                                      A                        50     mg                                            Lactose                  20     mg                                            Aerosil                  2      mg                                            Starch STA-RX 1500       18     mg                                            Calcium phosphate (CaHPO.sub.4)                                                                        25     mg                                            Microcrystalline cellulose                                                                             100    mg                                            Sodium acetate           15     mg                                            A                        50     mg                                            Microcrystalline cellulose                                                                             80     mg                                            Sodium acetate           25     mg                                            Auby-gel X 52            20     mg                                            Corn starch              50     mg                                            A                        50     mg                                            Microcrystalline cellulose                                                                             100    mg                                            Starch STA-RX 1500       99     mg                                            Aerosil                  1      mg                                            A                        50     mg                                            Corn starch              50     mg                                            Sodium acetate           15     mg                                            Magnesium stearate       2      mg                                            Aerosil                  3      mg                                            Starch STA-RX 1500       80     mg                                            Capsules.                                                                     A                        50     mg                                            Starch STA-RX 1500       94     mg                                            Magnesium stearate       1      mg                                            Sodium lauryl sulfate    5      mg                                            A                        50     mg                                            Microcrystalline cellulose                                                                             70     mg                                            Corn starch              30     mg                                            Peanut oil               0.01   mg                                            Sodium lauryl sulfate    5      mg                                            A                        50     mg                                            Sodium lauryl sulfate    5      mg                                            Microcrystalline cellulose                                                                             70     mg                                            Magnesium oxide          20     mg                                            A                        50     mg                                            Starch STA-RX 1500       100    mg                                            Magnesium stearate       1      mg                                            Sodium lauryl sulfate    10     mg                                            Microcrystalline cellulose                                                                             30     mg                                            Aerosil                  1      mg                                            Suppositories.                                                                A                        100    mg                                            Lidocaine                20     mg                                            Novata 299 grad.         2000   mg                                            A                        100    mg                                            Lidocaine                20     mg                                            Cutina GMS               100    mg                                            Novata B grad.           2000   mg                                            A                        100    mg                                            Witepsol S 58 grad.      2000   mg                                            ______________________________________                                    

The meaning of some terms used in the above galenic formulas is givenhereinafter:

Aerosil: trade name for finely divided silicium dioxide

Starch STA-RX 1500: corn starch

Auby-gel X 52: carragheen derivative

Lidocaine: trade name for lignocaine

Novata 299 grad.: mixture of saturated C₁₁ -C₁₇ fatty acid triglycerideswith partial glycerides of acetylated fatty acids.

Novata B grad.: mixture of tri-, di- and monoglycerides of saturated C₁₁-C₁₇ fatty acids.

Cutina GMS: glycerin monostearate

Witepsol S 58 grad.: mixture of C₁₂ -C₁₈ natural triglycerides.

Depending on the case and the kind of desired activity and of thespecific compound used, the amino-alcohol derivatives according to theinvention are administered at daily dosages of 50 to 3000 mgr.

We claim:
 1. An amino-alcohol derivative of the formula: ##STR67##wherein: R₁ represents an isopropylthio radical,R₂ represents a methylradical, R₃ represents an octyl radical or an alkyl radical C₁ -C₄substituted by a phenyl ring, R₄ represents an acyl group having theformula: ##STR68## wherein R₅ represents: a linear or ramified alkyl C₁-C₆,a linear or ramified alkyl radical C₁ -C₄ substituted by a phenyl orparamethoxyphenyl group, a cycloalkyl radical C₃ -C₆ or acycloalkylmethyl radical C₅ -C₆.
 2. A derivative as claimed in claim 1,wherein in formula I:(a) R₁ represents an isopropylthio radical, (b) R₂represents a methyl radical, (c) R₃ represents a n-octyl radical, (d) R₄represents an acyl group corresponding to the formula: ##STR69## inwhich R₅ represents: (d-1) a linear or ramified alkyl C₁ -C₆radical,(d-2) a cycloalkyl C₃ -C₆ radical, (d-3) a linear or ramifiedalkyl C₁ -C₂ radical substituted by a phenyl, para-methoxyphenyl orcyclohexyl group. 3.1-Butyryloxy-1-(4-isopropylthiophenyl)-2-n-octylaminopropane. 4.1-Cyclohexanoyloxy-1-(4-isopropylthiophenyl)-2-n-octylaminopropane. 5.p-Methoxyphenylacetyloxy-1-(4-isopropylthiophenyl)-2-n-octylaminopropane.6.1-Neopentylcarbonyloxy-1-(4-isopropylthiophenyl)-2-n-octylaminopropane.